Cerebrovascular disease is a condition in which the blood vessels circulating the brain are impaired by, for example, cerebral infarction, cerebral hemorrhage, head trauma, or subarachnoid hemorrage. As the flow of blood to the brain is interrupted or decreased by a cerebrovascular disease and the brain becomes ischemic, the nerve cells are damaged. Even if the patient narrowly escapes death, he or she suffers from sequelae of neuronal death caused by this impairment. Therapeutic agents for cerebrovascular disease may be classified into the agents which act against brain infarction, hemorrhage, etc. and those which inhibit said neuronal death.
It has recently become clear that once the brain tissue is brought into an ischemic state, even if the ischemia is transiently and the complete recovery of regional blood flow reinstates the normal energy metabolism and neural activity once, the final outcome is death of nerve cells. Such pathological changes of nerve cells, which characteristically occur predominantly in the hippocampus, manifest themselves in 3-4 days after ischemia and, therefore, are called delayed neuronal death. Moreover, even in the cerebral region not exposed to reperfusion, there are domains in which the blood flow is not completely interrupted but decreased. It is said that the nerve cells in such domains also succumb to death on prolongation of ischemia. This death of nerve cells could be blocked, the sequelae of a cerebrovascular disease following ischemia could be prevented.
It is known that the cerebral metabolism enhancer, propentofylline is effective against delayed neuronal death but, partly because of its side effects, is not a fully satisfactory medicine.
With therapeutic drugs in this field being the target, much research has been undertaken into inhibitors of excitatory amino acids. This is predicated on the concept of preventing ischemic death of neurons by inhibiting the excessive excitation of neurons following brain ischemia. It is well known that glutamic acid or glutamate is such an excitatory amino acid. As inhibitors of the excitatory amino acid, many glutamate antagonists which would specifically block the receptors of this amino acid and compounds which inhibit the release of glutamate are already known. The glutamate receptors are classified into the N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors and receptors other than said NMDA receptors (hereinafter referred to as non-NMDA receptors). As an NMDA antagonist, MK-801, for instance, is known, while YM-90K, for instance, is known to be a non-NMDA antagonist. As glutamate release inhibitors, 2,4-diamino-5-(2,3,5-trichlorophenyl)pyrimidine and 2,4-diamino-5-(2-chlorophenyl)pyrimidine are known [EP-A 459830; 6th SCI-RSC Medical Chemistry Symposium, Sep. 8-11, 1991].
Meanwhile, it is described in WO 92/04333 that a phenylpyrimidine derivative has learning-and-memory disorder improving activity and finds application in dementia. While various nerve systems have been impaired in dementia, it is known that the impairment of the cholinergic nervous system playing an important role in learning-and-memory is particularly serious. The phenylpyrimidine derivative disclosed in WO 92/04333 acts on the cholinergic nervous system and activates the residual nerve cells to ameliorate the learning-and-memory defects. This learning-and-memory improving action is quite different from the action to inhibit the onset of sequelae of a cerebrovascular disease through inhibition of neuronal death.
In addition to the above-mentioned compounds, a variety of pyrimidine derivatives have so far been reported. For example, Japanese Examined Publication S48-21949 discloses that 4-methyl-2-phenyl-6-[2-(4-phenylpiperazin-1-yl)ethyloxy]pyrimidine, among others, has a-sympatholytic activity (sedation, hypotension, and vasodilation). Moreover, it is reported in CA 100: 209733u and CA 106: 18488r that 4-[2-(N,N-dimethyl-amino)ethyloxy]-6-methyl(or phenyl)-2-phenylpyrimidine and 4-[2-(N,N-dimethylamino)ethylthio]-6-methyl(or phenyl)-2-phenylpyrimidine respectively have the property to amplify the action of phleomycin. Furthermore, it is reported in J. Med. Chem. 31(6), 1231-40 (1988) that 2-(2-dimethylamino)ethylthio-4-methyl(or unsubstituted)-6-phenyl(or aromatic heterocyclyl)-pyrimidine derivatives and 2-[2-(N,N-dimethylamino)ethoxy]-4-thienylpyrimidine derivatives amplify the action of bleomycin.